The chief objective of the planned research is the further definition of the genetic control of proteins on the complement system. In addition, the work planned seeks to study genetic variation in C2, BF, C4A, C4B, 21-OHA and 21-OHB and related DNA at define the overall size, gene copy number, gene order, and the extent of deletions and insertions in the class III MHC regions of extended and non-extended MHC haplotypes. We have postulated that at least 30% of normal caucasian MHC haplotypes have fixed DNA at least over the HLA-B-DR interval, including the class III genes, so that independent examples of them in unrelated persons are highly similar. We further postulate that it is these fixed or extended haplotypes that provide most of the HLA allele pairs that are in linkage disequilibrium and many of the MHC markers for a wide variety of diseases, including type I diabetes mellitus, gluten-sensitive enteropathy, pemphigus vulgaris, and 21-hydroxylase deficiency congenital adrenal hyperplasia. In the proposed work, we seek to determine which of the specific restriction fragment length polymorphisms and sequence variants in C2, BF, and C4 gene are found on specific extended haplotypes. We wish also to use these markers to define "new" extended haplotypes and fragments of them in the general population. Finally, we plan to try to explain the evolution and genetic mechanisms of origin of haplotypes with the relatively rare variant of the second component of complement, C2 B.